IRF4 haploinsufficiency in a family with Whipple's disease.
Elife
; 72018 03 14.
Article
em En
| MEDLINE
| ID: mdl-29537367
Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores Reguladores de Interferon
/
Tropheryma
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Haploinsuficiência
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Doença de Whipple
Tipo de estudo:
Prognostic_studies
Limite:
Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Elife
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
França
País de publicação:
Reino Unido